Regulation of Platelet Activation and Coagulation and Its Role in Vascular Injury and Arterial Thrombosis

Abstract

Hemostasis requires tightly regulated interaction of the coagulation system, platelets, blood cells, and vessel wall components at a site of vascular injury. Dysregulation of this response may result in excessive bleeding if the response is impaired, and pathologic thrombosis with vessel occlusion and tissue ischemia if the response is robust. Studies have elucidated the major molecular signaling pathways responsible for platelet activation and aggregation. Antithrombotic agents targeting these pathways are in clinical use. This review summarizes research examining mechanisms by which these multiple platelet signaling pathways are integrated at a site of vascular injury to produce an optimal hemostatic response.

Keywords: Antithrombotic agents; Arterial thrombosis; Coagulation; Hemostasis; Platelet activation; Vascular injury.

Figure 1. An updated model of the hemostatic response to vascular injury

This updated model takes into account the gradient of platelet activation observed emanating from the site of injury.

Figure 2. Regional architecture of a hemostatic plug

A) The properties of the core and shell regions of a hemostatic plug are described. B) The core and shell architecture develops as a result of local platelet agonist gradients that are shaped by physical forces within the platelet mass microenvironment.

Figure 3. A simplified illustration of the platelet signaling network

Platelets respond to chemical inputs in their local microenvironment via cell surface receptors that initiate multiple intracellular signaling cascades, ultimately leading to a graded series of platelet activation events, including shape change, integrin activation, aggregation, granule secretion and procoagulant activity. The degree of activation achieved by individual platelets within a hemostatic plug or thrombus is the net result of the integration of multiple inputs. For the GPCRs shown, the text in parentheses indicates the receptor(s) name for each agonist indicated. Red text indicates anti-platelet therapeutic targets.

Figure 4. The effect of anti-thrombotic agents on hemostatic plug architecture in an experimental model

A) Hemostatic plug formation in the mouse cremaster microcirculation is characterized by formation of a core of P-selectin positive platelets overlaid by a shell of P-selectin negative platelets. B) In the presence of the thrombin inhibitor hirudin, platelet accumulation is significantly attenuated and none of the adherent platelets become P-selectin positive. C) In contrast, a P2Y₁₂ antagonist results in a decrease in platelet accumulation in the outer shell region with no effect on full platelet activation in the core region. Data from Stalker TJ, Traxler EA, Wu J, et al. Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood. 2013;121(10):1875–1885.